Ceccarelli, Dora Maria (2016) Nuove acquisizioni di meccanismi molecolari nei tumori della vescica dei bovini associati ad infezione da papillomavirus. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: Italiano
Title: Nuove acquisizioni di meccanismi molecolari nei tumori della vescica dei bovini associati ad infezione da papillomavirus
Ceccarelli, Dora Mariadmceccarelli@libero.it
Date: 23 March 2016
Number of Pages: 71
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Veterinaria e Produzioni Animali
Scuola di dottorato: Scienze veterinarie per la produzione e la sanità
Dottorato: Biologia, patologia e igiene ambientale in medicina veterinaria
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
Cringoli, GiuseppeUNSPECIFIED
Roperto, FrancoUNSPECIFIED
Date: 23 March 2016
Number of Pages: 71
Uncontrolled Keywords: papillomavirus bovini, Mincle, ERas
Settori scientifico-disciplinari del MIUR: Area 07 - Scienze agrarie e veterinarie > VET/03 - Patologia generale e anatomia patologica veterinaria
Date Deposited: 11 Apr 2016 09:13
Last Modified: 31 Oct 2016 09:28
URI: http://www.fedoa.unina.it/id/eprint/11014


Urinary bladder tumors are very rare in cattle, accounting for 0.01% of all bovine malignancies. These tumors are, instead, commonly encountered in cows that grazed on pastures rich in bracken fern (Pteridium spp.). This plant contains toxic principles and its prolonged ingestion is responsible for a clinical syndrome known as chronic enzootic hematuria (CEH). It is believed that bovine deltapapillomaviruses have an important role in the bladder carcinogenesis frequently resulting in this syndrome. Chronic enzootic hematuria (CEH) occurs in several areas worldwide and is very common in Southern Italy, where bracken is particularly widespread. Papillomaviruses (PVs) are small, non-enveloped, dsDNA viruses with a well-defined tropism for cutaneous and mucosal epithelia in humans and a wide variety of domestic and wild animals. PVs are involved in the pathogenesis of animal and human tumors. The increasing interest to investigate PVs has led to the discovery of novel PV types. Therefore, the classification of papillomaviruses has been updated including 189 types after the incorporation of 28 novel human PV (HPV) and 48 novel animal PV types. Meanwhile, further new PV types such as Cervus elaphus papillomavirus (CePV1) and Equus asinus papillomavirus (EaPV1) have been described. Fourteen bovine papillomavirus (BPV) types (1 to 14) have been completely described and assigned to four genera. Bovine papillomavirus (BPVs) types 1/-2/-13 and 14 belong to the genus Deltapapillomavirus that show an epithelial and mesenchymal tropism as they have been detected in cutaneous and mucosa epithelial lining as well as in peripheral blood mononuclear and trophoblast cells. The major transforming protein encoded by deltapapillomaviruses is the 44-amino acid polypeptide E5. Bovine and human papillomavirus E5 proteins appear to be localized in the membranes of the endoplasmic reticulum, the Golgi apparatus and in the plasma membrane of the host cell. It has been shown that E5 oncoprotein of bovine papillomavirus is responsible for cell transformation via several pathways including the impairment of the V1-ATPase. In vitro studies have revealed that BPV E5 oncoprotein can impair the vacuolar H+-ATPase proton pump as it is able to bind to its component, the cellular protein 16 k ductin/subunit c of the V0 domain. This pump is essential for the acidification of the intracellular organelle compartments and may have an important role in protein sorting and processing. Dysfunction of the H+-ATPase proton pump can result in the perturbation of acidification of the endomembrane components and the cytosol. On the contrary, in vivo studies have shown that E5 interacts with the component D of the intracytoplasmic V1 domain of the H+-ATPase proton pump. Furthermore, it has been suggested that the 16 k protein allows E5 to bind to the platelet derived growth factor β receptor (PDGFβR), the activation of which has another important role in bovine bladder carcinogenesis. It has been shown that platelet derived growth factor β receptor (PDGFβR) is a key partner of bovine Deltapapillomavirus E5 oncoprotein both in vitro and in vivo carcinogenetic events. In the present work, we investigated the expression of ERas oncogene and functional mincle receptor in some urothelial tumors of the urinary bladder of cattle. Embryonic stem cell-expressed Ras (ERas), a member of the Ras family was initially found in mouse embryonic stem (ES) cells. ERas encodes a constitutively active form of GTPase that binds to and activates phosphatidylinositol 3 kinase (PI3K), which in turn phosphorylates and activates downstream targets such as Akt. For the first time, ERas upregulation and overexpression have been investigated in veterinary oncology. We have shown that ERas is a novel partner of Deltapapillomavirus E5 oncoprotein via the activated PDGFβR. This complex is involved in activation of PI3K signal transduction pathway leading to Akt phosphorylation. Indeed, it has a role in molecular cancer network of urothelial cells thus contributing to bovine papillomavirus-associated bladder carcinogenesis. In addiction, this was the first study, in veterinary oncology, about the expression of functional mincle receptor in neoplastic cells. Mincle, macrophage-inducible C-type lectin, is a member of C-type lectin receptors and it plays an important role in anti-mycobacterial and anti-fungal immunity. It was originally identified as a transcriptional target of NF-interleukin-6 (IL-6) mainly expressed on professional antigen-presenting cells (APCs), such as macrophages, dendritic cells (DCs), B cells, and neutrophils. The expression level of mincle in the steady-state condition is very low; however, it is strongly upregulated after exposure to different inflammatory signals. Mincle appears to be selectively associated with the Fc gamma receptor (FcγR) and activates macrophages to produce inflammatory cytokines and chemokines. It is known that Mincle associates with the adaptor protein FcγR required for initiation of signaling by binding Syk which, in turn, activates a signaling cascade through Card9 leading to the induction of cytokine and chemokine such as CXCL2. We detected mincle expression in papillomavirus-associated urothelial tumors of the urinary bladder in cattle. Morphologically, mincle protein was seen in urothelial neoplastic cells only but not in normal urothelial cells, which might mean that level of mincle expression is so low in steady-state condition as not to be detected with immunohistochemical procedures. Mincle expression in urothelial tumor cells warrants further study to better understand the role, if any, of this receptor in bladder cancer. Future studies will provide insights in the role of mincle receptor of urothelial cancer cells in antitumoral immunotherapy in comparative medicine as Bacillus Calmette-Guerin (BCG) is a attenuated, mincle-mediated mycobacterium used in the therapy of invasive bladder tumors in man.


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